1. Field of the Invention
This invention relates to a process for producing E-2-methyl-.alpha.,.beta.-unsaturated aldehydes useful as ultraviolet radiation absorbers and as intermediates in synthesizing the FK-506 immunosuppressant.
2. Brief Disclosures in the Art
The novel 23-membered tricyclo-macrolide FK-506 very recently isolated and characterized by Tanaka, Kuroda, and co-workers, see JACS, 109, pp. 5031, 1987, and EPO Publication No. 0,184,162, has been shown to possess exceptional immunosuppressive activity. The potential usefulness of such an agent in bone marrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate an effort towards the total synthesis of FK-506.
In conjunction with our efforts on the synthesis of FK-506, we were confronted with the need for the efficient conversion of the aldehyde 1 (see following Scheme I) to the E-2-methyl-.alpha.,.beta.-unsaturated aldehyde 2. For synthetic work in the project see: Askin, D.; Volante, R. P.; Reamer, R. A.; Ryan, K. M.; Shinkai, I. Tetrahedron Lett. 1988, 29, 277; Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 29, 281. ##STR1## After several unsuccessful attempts, we turned our attention to the procedure of Corey and coworkers as modified by Schlessinger et al., which employed ##STR2## the lithio-silylimine 3, illustrated above in Scheme II. For description of this reagent see: Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 7; Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P. Tetrahedron Lett. 1985, 26, 2391; Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman, R. J. J. Org. Chem. 1986, 54, 5111; DeWit, P. P. Rec. Trav. Chim. 1984, 103, 369; Takahashi, T.; Kitamura, K.; Tsuji, J. Tetrahedron Lett. 1983, 24, 4695; Derguini, F.; Caldwell, C. G.; Motto, M. G.; Balogh-Nair, V.; Nakanishi, K. J. Am. Chem. Soc. 1983, 105, 646. However, we found the use of this procedure was not practical as the ratio of E and Z isomers 2(E) and 2(Z) varied unpredictably from 2:1 to 10:1.
What is desired and needed in the art is an overall general synthesis utilizing readily available starting materials which will allow the synthesis of a high yield of the E isomer of 2 in a predictable and desirable E/Z isomer ratio.